Gastric and colonic formulations and methods for making and using them

ABSTRACT

In alternative embodiments, the invention provides compositions, e.g., formulations, used for gastric, gastrointestinal and/or colonic treatments or lavage, e.g., orthostatic lavage, e.g., for inducing the purgation (e.g., cleansing) of a gastrointestinal (GI) tract, including a colon; and methods for making and using them. In alternative embodiments, compositions and methods of the invention are used for the amelioration, treatment and/or prevention of constipation, for the treatment of abdominal pain, particularly non-specific abdominal pain, and diarrhea, including diarrhea caused by a drug side effect, a psychological condition, a disease or a condition such as Crohn&#39;s Disease, a poison, a toxin or an infection, e.g., a toxin-mediated traveler&#39;s diarrhea. In alternative embodiments, the invention provides pharmaceuticals and products (articles) of manufacture for delivering these compositions and formulations to an individual, e.g., a human or an animal.

TECHNICAL FIELD

This invention generally relates to medicine, pharmacology andbiochemistry. In alternative embodiments, the invention providescompositions, e.g., formulations or preparations, used for gastric,gastrointestinal and/or colonic treatments or lavage, e.g., orthostaticlavage, e.g., for inducing the purgation (e.g., cleansing) of agastrointestinal (GI) tract, including a colon; and methods for makingand using them. In alternative embodiments, compositions and methods ofthe invention are used for the amelioration, treatment and/or preventionof constipation or bloating, for the treatment of abdominal pain,particularly non-specific abdominal pain, and diarrhea, includingdiarrhea caused by a drug side effect, a psychological condition, adisease or a condition such as Crohn's Disease, a poison, a toxin or aninfection, e.g., a toxin-mediated traveler's diarrhea. In alternativeembodiments, the invention provides pharmaceuticals and products(articles) of manufacture for delivering these compositions andformulations to an individual, e.g., a human or an animal.

BACKGROUND

Electrolyte replenishment fluids are a beneficial factor for patientsundergoing preparation for colonoscopy. This poses a problem in thatmost oral rehydration solutions rely on glucose for co-transportation ofelectrolytes across the brush border of the small bowel utilizing theGLUT1 transport mechanism. Sugars however are known to causefermentation and production of combustible gases, unacceptable incolonoscopy where the use of electrocautery during polypectomy may leadto intracolonic explosion.

Due to these concerns there has been an increasing emphasis onmaintaining fluid and electrolyte homeostasis in the patient andavoidance of sugars. The challenge for developing safe and effectivebowel preparations has thus been to deliver a product that is: tolerabledue to acceptable taste and low volume of the preparation; safe bymaintaining electrolyte balance and fluid homeostasis; and, able tominimize side effects and lead to better patient acceptance andcompliance in consuming the purgative to better clean the bowel.

Several issues have become apparent with the use of conventional sugarsused in some current purgatives. In particular, the recorded cases ofintra-colonic combustion/explosion secondary to fermentation of thesugars by colon bacteria is a potential problem, although no instancesof such complications actually occurred using the describedpreparations. There were three factors which could contribute to apotential explosion during colonoscopy. These include the remainingcolonic bacterial load, propensity of the sugar to produce fermentationproducts such as methane and hydrogen, and the use of an electro-cauteryduring colonoscopy. This complication remains a feared but at most but atheoretical problem since only very smell quantities of sugar have beenincorporated into the purgative compositions described in the past.There is, nevertheless, continuing perception that some non-absorbablesugars such as mannitol or lactulose—may still, potentially pose anexplosive potential in spite of the addition of electrolytes and theaddition of such sugars, the side-effect profile—and while much morefavorable than before still included occasional patients who experiencedheadaches, suggesting a need for an improved electrolyte deliverysystem.

In some products, minimally degradable carbohydrates (sugars) are addedto the lavage composition to facilitate the physiological balance ofcoupled 1:1 transport of sodium and glucose in the small intestine so asto reduce electrolyte loss and concomitant fluid shifts. Thesecarbohydrates also have the ability to provide added purgative effect.

Definitions

The following are some definitions that may be helpful in understandingthe description of the present invention. These are intended as generaldefinitions and should in no way limit the scope of the presentinvention to those terms alone, but are put forth for a betterunderstanding of the following description.

Unless the context requires otherwise or specifically stated to thecontrary, integers, steps or elements of the invention recited herein assingular integers, steps or elements clearly encompass both singular andplural forms of the recited integers, steps or elements.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers, but not the exclusionof any other step or element or integer or group of elements orintegers. Thus, in the context of this specification, the term“comprising” means “including principally, but not necessarily solely”.

In some embodiments, equivalents are bioequivalent compounds orcompositions or compounds or compositions having substantially the sameproperties, e.g., substantially the same pharmacokinetic andpharmacodynamic properties.

The information provided herein and references cited are provided solelyto assist the understanding of the reader, and do not constitute anadmission that any or the references or information is prior art to thepresent invention.

SUMMARY

According to a first aspect of the present invention, there is provideda composition comprising:

(i) (A) a bisacodyl, or pyridin-2-ylmethanediyl)dibenzene-4,1-diyldiacetate, or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetateor, bioequivalent diphenylmethane or equivalent, or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent, and/or

-   -   (B) sodium picosulphate or equivalent;

(ii) an erythritol, or (2R,3S)-butane-1,2,3,4-tetraol, or equivalentisomers, or a sugar polyol substitute isoforms, or mixtures thereof; and

(iii) a pharmaceutically acceptable salt, or a salt acceptable for oralor enteral administration.

According to a second aspect of the present invention, there is provideda product (article) of manufacture comprising a composition of the firstaspect.

According to a third aspect of the present invention, there is provideda pharmaceutical composition, a preparation, or a formulation, or food,feed, supplement or additive, comprising a imposition of the firstaspect.

According to a fourth aspect of the present invention, there is provideda method for performing a colonoscopy; an enteroscopy or endoscopy; acapsule endoscopy; a viewing of the intestinal or colonic mucosa; asurgical or an investigative, therapeutic or ameliorative, prophylacticor radiological procedure involving the intestine or colon; comprising:

(a) administering a composition of the first aspect or a product(article) of manufacture of the second aspect, or a pharmaceuticalcomposition, preparation or formulation, or food, feed, supplement oradditive, of the third aspect, to an individual in need thereof.

According to a fifth aspect of the present invention, there is provideda method for the amelioration, treatment and/or prevention ofconstipation or bloating, for the treatment of abdominal pain,particularly non-specific abdominal pain, and diarrhea, includingdiarrhea caused by a drug side effect, a psychological condition, adisease or a condition such as Crohn's Disease, a poison, a toxin or aninfection, e.g., a toxin-mediated traveler's diarrhea, comprisingadministering a composition of the first aspect, or a product (article)of manufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, to an individual in need thereof.

According to a sixth aspect of the present invention, there is provideda method for the amelioration or treatment of a bowel disease,comprising administering a composition of the first aspect or a product(article) of manufacture of the second aspect, or a pharmaceuticalcomposition, preparation or formulation, or food, feed, supplement oradditive, of the third aspect, to an individual in need thereof.

According to a seventh aspect of the present invention, there isprovided a method for the amelioration or treatment of a bowel diseaseor condition having a bowel dysfunction component, an inflammatory boweldisease (IBD), Crohn's disease, a hepatic encephalopathy, an enteritis,a colitis, an irritable bowel syndrome (IBS), a fibromyalgia (FM), achronic fatigue syndrome (CFS), a depression, an attentiondeficit/hyperactivity disorder (ADHD), a multiple sclerosis (MS), asystemic lupus erythematosus (SLE), a travelers' diarrhea, a smallintestinal bacterial overgrowth, a chronic pancreatitis, or a pancreaticinsufficiency, comprising administration of therapeutically effectiveamount of the composition of the first aspect, or a product (article) ofmanufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, to an individual in need thereof.

According to an eighth aspect of the present invention, there isprovided a package or kit comprising combination of at least twoformulations, wherein one (a first) formulation is contained in a firstcontainer and a second formulation is contained in a second container,and the formulations are designed to be taken in sequence as part of atreatment or colonoscopy preparation regimen, wherein a patient isadministered or instructed to take the contents of a first containerbefore the contents of a second container, wherein the first or secondformulation is a composition of the first aspect or a product (article)of manufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect.

According to a tenth aspect of the present invention, there is provideda method for administering a combination of (at least two) differentformulations that are designed to be taken in as part of a treatment ora colonoscopy preparation regimen, comprising administering the contentsof the first container, then several hours later or the next day thecontents of the second container, wherein the first and second containerare in the package or kit of the eighth aspect.

According to an eleventh aspect of the present invention, there isprovided a pharmaceutical composition, a preparation, or a formulationcomprising a composition of the first aspect or a product (article) ofmanufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, wherein the pharmaceutical composition, a preparation,or a formulation is manufactured, labeled or formulated for theamelioration or treatment of a bowel disease, wherein optionally thebowel disease or condition having a bowel dysfunction component,comprises: an inflammatory bowel disease (ISD), Crohn's disease, hepaticencephalopathy, enteritis, colitis, irritable bowel syndrome (IBS),fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attentiondeficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemiclupus erythernatosus (SLE), travelers' diarrhea, small intestinalbacterial overgrowth, chronic pancreatitis, or a pancreaticinsufficiency.

According to a twelfth aspect of the present invention, there isprovided use of a composition of the first aspect or a product (article)of manufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, for manufacture of a medicament.

According to a thirteenth aspect of the present invention, there isprovided use of a composition of the first aspect or a product (article)of manufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, in the preparation of a medicament for theamelioration, treatment and/or prevention of constipation or bloating,for the treatment of abdominal pain, particularly non-specific abdominalpain, and diarrhea, including diarrhea caused by a drug side effect, apsychological condition, a disease or a condition such as Crohn'sDisease, a poison, a toxin or an infection, e.g., a toxin-mediatedtravelers diarrhea.

According to a fourteenth aspect of the present invention, there isprovided use of a composition of the first aspect or a product (article)of manufacture of the second aspect or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, in the preparation of a medicament for theamelioration or treatment of a bowel disease, wherein optionally thebowel disease or condition having a bowel dysfunction component,comprises: an inflammatory bowel disease (IBD), Crohn's disease, hepaticencephalopathy, enteritis, colitis, irritable bowel syndrome (IBS),fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attentiondeficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemiclupus erythematosus (SLE), travelers' diarrhea, small intestinalbacterial overgrowth, chronic pancreatitis, or a pancreaticinsufficiency.

According to a fifteenth aspect of the present invention, there isprovided a composition of the first aspect or a product (article) ofmanufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, for use in the amelioration, treatment and/orprevention of constipation or bloating, for use in the treatment ofabdominal pain, particularly non-specific abdominal pain, and diarrhea,including diarrhea caused by a drug side effect, a psychologicalcondition, a disease or a condition such as Crohn's Disease, a poison, atoxin or an infection, e.g., a toxin-mediated travelers diarrhea.

According to a sixteenth aspect of the present invention, there isprovided a composition of the first aspect or a product (article) ofmanufacture of the second aspect, or a pharmaceutical composition,preparation or formulation, or food, feed, supplement or additive, ofthe third aspect, for use in the amelioration or treatment of a boweldisease, wherein optionally the bowel disease or condition having abowel dysfunction component, comprises: an inflammatory bowel disease(IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis,irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatiguesyndrome (CFS), depression, attention deficit/hyperactivity disorder(ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE),travelers' diarrhea, small intestinal bacterial overgrowth, chronicpancreatitis, or a pancreatic insufficiency.

In alternative embodiments, the invention provides compositions(including formulations, pharmaceutical compositions, foods, feeds,supplements, products of manufacture, and the like, and methods formaking and using them) comprising:

(a) (i) (A) a bisacodyl, or (pyridin-2-ylmethanediyl)dibenzene-4,1-diyldiacetate, or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate,or bioequivalent diphenylmethane or equivalent or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent,

wherein optionally the composition comprises between about 1, 5, 10, 15,20, 25, 30, 35, 40, 45 to 50 milligram (mg) to about 100, 150, 200, 240,250, 300, 350, 400, 450, 500, 550, 600, 650, 740, 750, 800, 850, 900,950 or 1000 or more milligrams (mg), or between about milligrams (mg) toabout milligrams (mg), or the composition comprises about 1, 2, 3, 4, 5,6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 60,55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140,150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 350,400, 450 or 500 or more mgs of:

a bisacodyl, or (pyridin-2-ylmethanediyl)dibenzene-4,1-diyl diacetate,or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate, orbioequivalent diphenylmethane or equivalent, or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent, or

wherein optionally the composition comprises between about 5, 10, 20,30, 40, or 50 mg to about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more grams(g) of a bisacodyl or (pyridin-2-ylmethanediyl)dibenzene-4,1-diyldiacetate, or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate,or bioequivalent diphenylmethane or equivalent or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent, or between about 75, 80, 85, 90 or 100 mg toabout 150 to 200 mg (optionally, for a normal patient) bisacodyl orpyridin-2-ylmethanediyl)dibenzene-4,1-diyl diacetate, or4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate, orbioequivalent diphenylmethane or equivalent or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent, or between about 100, 110, 120, 130, 140 or 150mg to about 1, 2, 3, 4 or 4.5 g or more bisacodyl orpyridin-2-ylmethanediyl)dibenzene-4,1-diyl diacetate, or4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate, orbioequivalent diphenylmethane or equivalent or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(41H)-one), orbisoxatin acetate, or equivalent for a constipated patient, of:

a bisacodyl, or (pyridin-2-ylmethanediyl)dibenzene-4,1-diyl diacetate,or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate, orbioequivalent diphenylmethane or equivalent, or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent,

wherein optionally the composition comprises between about 10, 20, 30,40, 50, 75, 80, 85, 90, 100 or 150 mg to about 100, 150, 200, 250, 300,350, 400, 450, or 500 or more mg, or between about 50, 75, 80, 85, 90,100 or 150 mg to about 150 to 200 mg (e.g., for a normal patient), orbetween about 100 to 250 mg, or between about 100, 110, 120, 130, 140 or150 mg to about 1, 2, 3, 4 or 4.5g or more for a constipated patient, of

a bisacodyl, or (pyridin2-ylmethanediyl)dibenzene-4,1-diyl diacetate, or4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate, orbioequivalent diphenylmethane or equivalent or a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxezin-3(4H)-one), or bisoxatinacetate, or equivalent, or

(A1) a bisacodyl, or pyridin-2-ylmethanediyl)dibenzene-4,1-diyldiacetate, or 4,4′-(pyridin-2-ylmethylene) bis(4,1-phenylene) diacetate,or bioequivalent diphenylmethane, at or less than about 25 mg, 24 mg, 23mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mgor 1 mg or less, or are between about 1 and mg per dosage;

and optionally the bisacodyl is DULCOLAX™, DUROLAX™, FLEET™, ALOPHEN™ orCORRECTOL™; and optionally the bisoxatin is LAXONALIN™, MARATAN™,TALSIS™, TASIS™, WYLAXINE™ and/or

(B) a sodium picosulphate or equivalent,

wherein optionally the composition comprises between about 1 milligram(mg) to about 100 milligrams (mg), or between about 5 milligrams (mg) toabout 15 milligrams (mg), or the composition comprises about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 ormore mgs of a sodium picosulphate or equivalent;

(II) erythritol, or (2R,3S)-butane-1,2,3,4-tetraol, or equivalentisomers or sugar or polyol substitute isoforms,

wherein optionally the composition comprises between about 1 to about 40grams of erythritol (or equivalent isomers or sugar substitute orsynthetic isoforms); or, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 or more grams, of erythritol(or equivalent isomers or sugar substitute or synthetic isoforms); and

(III) a pharmaceutically acceptable salt, or a salt acceptable for oralor enteral administration;

wherein optionally the composition comprises between about 1 to about 40grams, or between about 8 to 15 grams, or between about 15 to 28 grams,of salt or salts per day; or, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 or more grams, of salt orsalts,

wherein the composition is formulated for use as a purgative, a coloniccleanser, or for orthostatic lavage, or

(b) the composition of (a), wherein:

-   -   (1)(i) the salt is a water-soluble salt; (ii) optionally the        erythritol, equivalent isomer or sugar or polyol substitute        isoform, is present in an amount, by weight, of from about 1 to        about 3 times the weight of the salt ions in (each unit dose of)        the composition; (iii) optionally the salt comprises a        water-soluble potassium salt in an amount, by weight, of from        about 0.05 to about 1 times the weight of a sodium salt in the        composition; or (iv) optionally the salt comprises a        water-soluble magnesium salt, wherein the weight of magnesium        ions in the composition is from about 0.1 to about 10 times the        weight of sodium ions in the composition; or    -   (2) the salt comprises at least one of a calcium salt, a calcium        carbonate, a calcium acetate, a citrate salt, a calcium citrate,        a magnesium salt, a magnesium sulphate, a magnesium citrate, a        monobasic sodium phosphate, dibasic sodium phosphate, and/or        tribasic sodium phosphate, a magnesium phosphate, a sodium salt,        a sodium sulphate, a sodium chloride, a sodium gluconate, a        sodium citrate, a sodium aspartate, a potassium salt, a        potassium gluconate, a potassium tartrate, a potassium chloride,        an acetate salt, an adipate salt, an alginate salt, an aspartate        salt, a benzoate sail, a benzenesulfonate salt, a bisulfate        salt, a butyrate salt, a camphorate salt, a camphor sulfonate        salt, a digluconate salt, a glycerophosphate salt, a hemisulfate        salt, a heptanoate salt, a hexanoate salt, a fumarate salt, a        hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a        2-hydroxyethansulfonate (isothlonate) salt, a lactate salt, a        maleate salt, a methane sulfonate salt, a nicotinate salt, a        2-naphthalene sulfonate salt, an oxalate salt, a palmitoate        salt, a pectinate salt, a persulfate salt, a 3-phenylpropionate        salt, a picrate salt, a pivalate salt, a propionate salt, a        succinate salt, a tartrate salt, a thiocyanate salt, a phosphate        salt, a glutamate salt, a bicarbonate salt, a p-toluenesulfonate        salt, a undecanoate salt, or any equivalent salt, or any salt as        described in “Handbook of Pharmaceutical Salts: Properties,        Selection and Use”, Weinheim, N.Y.: VHCA; Wiley-VCH, 2002, or        any mixture thereof;

(c) the composition of (a) or (b), wherein the composition ismanufactured, labeled or formulated as a liquid; a suspension, a spray,a gel, a geltab, a semisolid, a tablet, a lozenge, a sachet or acapsule;

(d) the composition of any of (a) to (c), wherein the composition ismanufactured, labeled or formulated as a preparation, a pharmaceuticalor a formulation for human or animal use;

(e) the composition of (d), wherein the animal use is for a veterinaryuse; or

(f) the composition of any of (a) to (e), wherein the composition ismanufactured, labeled or formulated for use as a purgative, or fororthostatic lavage.

In alternative embodiments, a composition of the invention furthercomprises:

(a) a defoaming agent, a surfactant agent, a lubricant, an acidneutralizer, a marker, a cell marker, a drug, an antibiotic and/or acontrast agent;

(b) the composition of (a), wherein the marker comprises ahexaminolevulinate, an indigo carmine or a methylene blue or anequivalent cell marker;

(c) the composition of (a), wherein the marker comprises an antibodyspecific for a normal or abnormal cell phenotype or genotype, or acancer cell or a polyp;

(d) the composition of (a), wherein the surfactant agent comprises asimethicone or any mixture of polydimethylsiloxane and silica gel, orequivalent;

(e) the composition of (a), wherein the lubricant comprises a magnesiumstearate, a hyaluronic acid, a glycerol and/or a silicone, and/or thelubricant comprises an encapsulating material, wherein the encapsulatingmaterial acts as a capsule or covering for a preparation of thecomposition;

(f) the composition of (a), wherein the defoaming agent comprises asilicone and/or a glycerol;

(g) the composition of (f), wherein the acid neutralizer comprises awater-soluble acid neutralizer, which optionally comprises atromethamine, a meglumine, a sodium bicarbonate, a sodium carbonate, orany combination thereof, or the acid neutralizer comprises awater-insoluble acid neutralizer, which optionally comprises a magnesiumhydroxide, an aluminum hydroxide, a dihydroxy aluminum sodium carbonate,a calcium carbonate, and any combination thereof;

(h) the composition of (a), wherein the antibiotic is one or more of arifamycin, aminoglycoside, amphenicol, ansamycin, beta-lactam,carbapertem, cephalosporin, cephamycin, monobactam, oxacephem, alincosamide antibiotic (e.g., clindamycin, lincomycin), a macrolideantibiotic (e.g., an azithromycin, clarithromycin, dirithromycin,erythromycin), glycopeptide antibiotic (e.g., a vancomycin, telcoplanin,telavancin, bleomycin, ramoplanin and/or a decaplartin), a polypeptideantibiotic (e.g., actinomycin, such as actinomycin D; bacitracin),tetracycline, or a 2,4-diaminopyrimidine class antibiotic;

(i) the composition of any of (a) to (h), further comprising at leastone non-osmotic purgative, which optionally comprises a mineral oil,aloe, bisoxatin, bisacodyl, sodium picosulfate or equivalent,casanthranol, cascara, castor oil, danthron, dehydrocholic acid,phenolphthalein, sennosides, docusate, bethanachol, colchicines,misoprostol, cisapride, norcisapride, paraffin, thein and/or tegaserodor equivalents; and/or further comprising at least one bulk-formingpurgative, which optionally comprises a methylcellulose, sodiumcarboxymethyl cellulose, bran, psyllium, sterculia and/or testaispaghula or equivalents;

(j) the composition of any of (a) to (i), further comprising at leastone halogenated carbohydrate, which optionally comprises a halogenatedmonosaccharide, halogenated polysaccharide, halogenated oligosaccharide,halogenated disaccharide, and/or halogenated trisaccharide, wherein thehalogen optionally comprises a fluorine, chlorine, bromine, iodine,and/or an astatine;

(k) the composition of any of (a) to (j), further comprising at leastone dispersal agent, buffering agent, sweetening agent, debitteringagent, flavoring agent, pH stabilizer, acidifying agent, preservative,desweetening agent and/or coloring agent; or

(l) the composition of any of (a) to (i), further comprising at leastone disintegrant, which optionally comprises a natural starch, a maizestarch or potato starch; a directly compressible starch; a modified orpre gelatinized starch, a carboxymethyl starch, a sodium starchglycolate; a natural or a chemically-modified cellulose, a crosslinkedsodium carboxymethyl cellulose, a croscamiellose sodium, a lowsubstituted hydroxypropyl cellulose; a microcrystalline cellulose; agum, an agar gum, a guar gum; an alginic acid or salts thereof; anacetate or a citrate; an aluminum oxide; a synthetic polymer, across-linked polyvinylpyrrolidone and/or a crospovidone; er

(m) the composition of any of (a) to (i), further comprising at leastone vitamin, mineral and/or dietary supplement, wherein optionally thevitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenicacid, pyridoxine, biotin, folic acid, vitamin B₁₂, lipoic acid, ascorbicacid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, acarnitine, and/or an alpha, beta and/or gamma carotene.

in alternative embodiments, the invention provides a product (article)of manufacture comprising a composition of the invention.

In alternative embodiments, the invention provides a pharmaceuticalcomposition, a preparation, or a formulation, or a feed, food orsupplement, comprising a composition of the invention. In alternativeembodiments, the pharmaceutical composition, preparation, formulation,feed, food or supplement comprises:

(a) a composition of the invention;

(b) the pharmaceutical composition, preparation or formulation of (a),wherein the composition is manufactured, labeled or formulated as aliquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet,a lozenge or a capsule, or as an enteral formulation;

(c) the pharmaceutical composition, preparation or formulation of (a) or(b), wherein the pharmaceutical composition or a formulation ismanufactured with an encapsulating material, and optionally theencapsulating material comprises a lubricant;

(d) the pharmaceutical composition, a preparation, or a formulation ofany of (a) to (c), wherein the pharmaceutical composition, apreparation, or a formulation is manufactured, labeled or formulated forhuman or animal use;

(e) the pharmaceutical composition, a preparation, or a formulation of(d), wherein the animal use is for a veterinary use;

(f) the pharmaceutical composition, a preparation, or a formulation ofany of (a) to (e), wherein the pharmaceutical composition, apreparation, or a formulation is manufactured, labeled or formulated foruse as a purgative, or for orthostatic lavage; or for use with (e.g., inpreparation for) a colonoscopy; an enteroscopy or endoscopy; a capsuleendoscopy; a viewing of the intestinal or colonic mucosa; a surgical oran investigative, therapeutic or ameliorative, prophylactic orradiological procedure involving the intestine or colon;

(g) the pharmaceutical composition, a preparation, or a formulation ofany of (a) to (e), wherein the pharmaceutical composition, apreparation, or a formulation is manufactured, labeled or formulated forthe amelioration, treatment and/or prevention of constipation orbloating, for the treatment of abdominal pain, particularly non-specificabdominal pain, and diarrhea, including diarrhea caused by a drug sideeffect, a psychological condition, a disease or a condition such asCrohn's Disease, a poison, a toxin or an infection, e.g., atoxin-mediated traveler's diarrhea; or

(h) the pharmaceutical composition, a preparation, or a formulation ofany of (a) to (e), wherein the pharmaceutical composition, apreparation, or a formulation is manufactured, labeled or formulated forthe amelioration or treatment of a bowel disease, wherein optionally thebowel disease or condition having a bowel dysfunction component,comprises: an inflammatory bowel disease (IBD), Crohn's disease, hepaticencephalopathy, enteritis, colitis, irritable bowel syndrome (IBS),fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attentiondeficit/hypractivity disorder (ADHD), multiple sclerosis (MS), systemiclupus erythematosus (SLE), travelers' diarrhea, small intestinalbacterial overgrowth, chronic pancreatitis, or a pancreaticinsufficiency.

The invention provides methods for performing a colonoscopy; anenteroscopy or endoscopy; a capsule endoscopy; a viewing of theintestinal or colonic mucosa; a surgical or an investigative,therapeutic or ameliorative, prophylactic or radiological procedureinvolving the intestine or colon; comprising:

(a) administering a composition of the invention, or a product (article)of manufacture of the invention, or a pharmaceutical composition,preparation or formulation, or food, feed or supplement, of theinvention, to an individual in need thereof; or

(b) the method of (a), wherein the individual is a human or an animal.

The invention provides methods for the amelioration, treatment and/orprevention of constipation or bloating, for the treatment of abdominalpain, particularly non-specific abdominal pain, and diarrhea, includingdiarrhea caused by a drug side effect, a psychological condition, adisease or a condition such as Crohn's Disease, a poison, a toxin or aninfection, e.g., a toxin-mediated travelers diarrhea, comprisingadministering a composition of the invention, or a product (article) ofmanufacture of the invention, or a pharmaceutical composition,preparation or formulation of the invention, to an individual in needthereof.

In alternative embodiments, the constipation or bloating is due to atleast one of: travel; change in day routine; lack of exercise;immobility caused by injury, illness, or aging; dehydration; irritablebowel syndrome; pregnancy; diabetes; hypothyroidism; hypercalcemia;cancer of the colon or rectum; uterine prolapse; vaginal vault prolapse;rectal prolapse; scarring from surgery; injury of the colon or rectum;Parkinson's disease; multiple sclerosis; stroke; hemorrhoids or analfissures; delaying bowel movements; anxiety; depression; eatingdisorders; and/or obsessive-compulsive disorder, coeliac disease,muscular dystrophy, myotonic dystrophy, non-specific abdominal pain, ora neurological condition or any cause of constipation.

The invention provides methods for the amelioration or treatment of abowel disease comprising use of a composition of the invention, whereinoptionally the bowel disease or condition having a bowel dysfunctioncomponent, comprises: an inflammatory bowel disease (IBD), Crohn'sdisease, hepatic encephalopathy, enteritis, colitis, irritable bowelsyndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS),depression, attention deficit/hyperactivity disorder (ADHD), multiplesclerosis (MS), systemic lupus erythematosus (SLE), travelers' diarrhea,small intestinal bacterial overgrowth, chronic pancreatitis, or apancreatic insufficiency.

The invention provides packages or kits (or equivalents) comprising acombination of at least two formulations, wherein one (a first)formulation contained in a first container (e.g., a bottle or blisterpack or equivalent) and a second formulation is contained in a secondcontainer (e.g., a bottle or blister pack or equivalent), and theformulations are designed to be taken in sequence as part of a treatmentor colonoscopy preparation regimen, wherein a patient is administered orinstructed to take the contents of a first container (e.g., a bottle,blister pack, and the like) before the contents of a second container.

In alternative embodiments of the packages or kits, the contents of thefirst container comprises or consists of capsules (or pills, tablets,geltabs, and the like) comprising the following formulation: Bisacodylor Bisoxatin, Magnesium sulphate, Sodium sulphate, Potassium gluconate,Sodium chloride and Erythritol, optionally in the following exemplaryamounts:

First Container

Bisacodyl or Bisoxatin   10 mg Magnesium sulphate 2.95 g Sodium sulphate6.32 g Potassium gluconate 1.26 g Sodium chloride 1.26 g Erythritol 1.26g

and optionally these capsules are a different color and/or shape thanthe capsules (or pills, tablets, geltabs, and the like) in the secondformulation (contained in the second container),

and optionally the first container (e.g., a bottle) comprises betweenabout 10 to 40 or more capsules, e.g., 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or morecapsules.

In alternative embodiments of the packages or kits, the contents of thesecond container comprises or consists of capsules (or pills, tablets,geltabs, and the like) comprising the following formulation: Magnesiumsulphate, Sodium sulphate, Potassium gluconate, Sodium chloride andErythritol, optionally in the following exemplary amounts:

Second Container

Magnesium sulphate 4.05 g Sodium sulphate 8.68 g Potassium gluconate1.74 g Sodium chloride 1.74 g Erythritol 1.74 g,

and optionally the second container comprises between about 2 to 30 ormore capsules, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or morecapsules.

In alternative embodiments of the packages or kits, the kits comprise asingle container that comprises or consists of capsules (or pills,tablets, geltabs, and the like) comprising the following formulation:Bisoxatin, Magnesium sulphate, Sodium sulphate, Potassium gluconate,Sodium chloride and Erythritol, optionally in the following exemplaryamounts:

Bisoxatin 240 mg    Magnesium sulphate 7 gm Sodium sulphate 3 gmPotassium gluconate 3 gm Sodium chloride 4 gm Erythritol 2 gm

and optionally the container (e.g., a bottle) comprises between about 10to 40 or more capsules, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or more capsules.

In alternative embodiments of the packages or kits, the contents of thesecond container comprises or consists of capsules (or pills, tablets,geltabs, and the like) comprising the following formulation: Magnesiumsulphate, Sodium sulphate, Potassium gluconate, Sodium chloride andElythritol, optionally in the following exemplary amounts:

Second Container

Magnesium sulphate 4.05 g Sodium sulphate 8.68 g Potassium gluconate1.74 g Sodium chloride 1.74 g Erythritol 1.74 g,

and optionally the second container would have between about 2 to 30 ormore capsules, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 26, 26, 27, 28, 29, 30, 31, 32 or morecapsules.

The invention provides methods for administering a combination of (atleast two) different formulations that are designed to be taken insequence (a moiled “split protocor”) as part of a treatment or acolonosoopy preparation regimen, comprising administering (orinstructing to the patient to self-administer) the contents of the firstcontainer, then several hours later (e.g., between about 6 to 24 hourslater) or the next day (e.g., the morning of the procedure, e.g., acolonoscopy) the contents of the second container, wherein the first andsecond container are in the package or kit of the invention,

and optionally, the first container (e.g., a bottle) comprises capsules(or pills, tablets, geltabs, and the like) has exemplary formulation 11,and the second container (e.g., a bottle) comprises capsules (or pills,tablets, geltabs, and the like) having exemplary formulation 12, and thefirst container has about 16 capsules to be taken or administered first,and the second container has about 22 capsules to be taken later, e.g.,several hours later (e.g., between about 8 to 24 hours later) or thenext day (e.g., the morning of the procedure, e.g., a colonoscopy),

and optionally, the first container comprises capsules (or pills,tablets, geltabs, and the like) having exemplary formulation 11, and thesecond container comprises capsules (or pills, tablets, geltabs, and thelike) having exemplary formulation 12, and the first container has about32 capsules to be taken or administered first, and the second container(e.g., a bottle) has about 6 capsules to be taken later, e.g., severalhours later (e.g., between about 6 to 24 hours later) or the next day(e.g., the morning of the procedure, e.g., a colonoscopy).

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

All publications, patents, patent applications cited herein are herebyexpressly incorporated by reference for all purposes.

DETAILED DESCRIPTION

In alternative embodiments, the invention provides compositions, e.g.,formulations and pharmaceutical preparations, used for gastric,gastrointestinal and/or colonic treatments or lavage, e.g., orthostetklavage, e.g., for inducing the purgation (e.g., cleansing) of agastrointestinal (GI) tract, including a colon; and methods for makingand using them, in alternative embodiments, compositions and methods ofthe invention are used for the amelioration, treatment and/or preventionof constipation or bloating, for the treatment of abdominal pain,particularly non-specific abdominal pain, and diarrhea, includingdiarrhea caused by a drug side effect, a psychological condition, adisease or a condition such as Crohn's Disease, a poison, a toxin or aninfection, e.g., a toxin-mediated traveler's diarrhea. In alternativeembodiments, the invention provides pharmaceuticals and products(articles) of manufacture for delivering these compositions andformulations to an individual, e.g., a human or an animal.

In alternative embodiments, the invention provides compositionscomprising the four-carbon (4-carbon) chain polyol known as erythritol,or (2R,3S)-butane-1,2,3,4-tetraol, or equivalent isomers or sugar orpolyol substitute isoforms, and low dosages of bisacodyl or a bisoxatin.

In one embodiment, the erythritol is produced from glucose byfermentation with a yeast such as Moniliella pollinis. Erythritoldemonstrates none or minimal fermentation by colonic bacteria and onlynon-combustible short chain fatty acids and CO₂ are produced in smallamounts, see e.g., Noda (1992) J. Nutri 122:1266-1272. There have beenno recorded significant human gastroenterological side effects aterythritol doses of up to 1000 mg/kg body weight/day. Absorbederythritol is not metabolized systemically and is excreted unchanged inurine, further improving its safety profile as it will not causeinteractions or cause metabolic disturbances. Erythritol has no effecton 24 hour urine output of creatinine, urea or electrolytes (e.g.,sodium, potassium, chloride, phosphate) in direct contrast to phosphatelavage preparations.

In alternative embodiments, the “low” dosages of bisacodyl are at orless than about 25 mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg,17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg or 1 mg or less, or are between about 1and 25 mg per dosage. When erythritol is added to a purgative agent suchas bisacodyl, which promotes evacuation of the colon by alteringintestinal fluid and electrolyte absorption and smooth musclecontractility, we have discovered an unexpected enhanced purgativeaction. Bisacodyl has on rare occasions been associated with ischemiccolitis in doses of 20 mg, and less frequently with the 10 mg tabletform in combination with HALFLYTELY™ (Braintree Labs, Braintree, Ma.).No ischemic colitis has been consistently observed or reported usingbisacodyl in spite of its widespread chronic use at a lower dosage rangeoften on a daily basis for treatment of constipation or bloating overlong periods.

In alternative embodiments, additional ingredients, reagents, agentsand/or biologics are included in a composition of the invention. Forexample, a composition, e.g., a purgative of the invention for coloniclavage, designed or manufactured as a vehicle for the delivery of one ormore markers, e.g., markers that can highlight the presence of a normalor an abnormal cell type, e.g., a colonic polyp. This embodiment allowsfor a higher detection rate of polyps during a colonoscopy.

In one embodiment, a hexaminolevulinate is added to a composition of theinvention to mark polyps with fluorescence, e.g., prior to acolonoscopy, so as to facilitate enhanced polyp detection. Anappropriate blue excitation light of 375-440 nm can be used. Thispreparation of the invention can enhance the value of the bowelpreparation by also improving the polyp detection rate, as has beenfound in the case of bladder cancers using this marker. In alternativeembodiments, other markers such as Indigo carmine or methylene blue aresimilarly incorporated into a formulation of the invention, e.g., tofurther improve colonic polyp detection rates without the need forblue-light colonoscopy.

In one embodiment, adequate visualization of the bowel lumen of a colonis further enhanced by addition of a simethicone or similar surfactantagent to a formulation or preparation of the invention. This can reducebubbling often seen at colonoscopy that obscures visualization.

In one embodiment, a lubricant is added to a formulation or preparationof the invention to e.g. facilitate the passage of a colonoscope byreducing mucosal resistance. In alternative embodiments, lubricants usedin formulations or preparations of the invention comprise hyaluronicacid, glycerol and/or silicone. In one embodiment, an encapsulatingsubstance dissolves in the gut to form a lubricant; as in onealternative aspect there can be between about 20 to 40 capsules (orother unit dosage form, e.g., a geltab, tablet, etc.) administered, inone embodiment, a specialized encapsulating material is used as alubricant.

Silicones that can be used to manufacture formulations or preparationsof the invention are polymers that include silicon together with carbon,hydrogen, oxygen, and sometimes other chemical elements; and can have athermal stability, e.g., a constancy of properties over a wide operatingrange of between about −100 to 250° C.; and, although not a hydrophobe,silicon is able to repel water and does not stick. With low chemicalreactivity and low toxicity, silicone does not support microbiologicalgrowth. During polymerization, this reaction can evolve a hazardoushydrogen chloride gas. For medical uses, the invention can use a processwhere the chlorine atoms in the silane precursor are replaced withacetate groups. In one aspect, silicones are used as a defoamer becauseof a low water solubility and good spreading properties. In one aspect,gelatin capsules incorporating glycerol are used; they can furtherassist as a lubricant and defoamer.

From systematic clinical studies we have now discovered that alavage-powdered composition comprising stimulants such as bisacodyl orsodium picosulphate or a bisoxalin, at least one of various salts e.g.magnesium sulphate, sodium sulphate, potassium gluconate, and the polyolerythritol (or (2R,3S)-butane-1,2,3,44tetraol) or equivalents, is notonly capable of cleansing the bowel effectively while using a smallnumber of capsules but has other major improvement features. Itmaintains Its hypertonicity when it dissolves in the stomach and when itis followed by the required volume of water. Its bowel cleansing actionis quite superior to the current bowel cleansing products on the market,even in constipated or bloated patients. In alternative embodiments,these components are used in doses (e.g., unit dosages) of between 1 mgand 30 grams or more, or at a dosage of about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29 or 30 grams or more, within a composition of the invention, e.g.,a liquid (e.g., formulated as a drink, a soup or a soup-likecomposition), a suspension, a gel, a geltab, a semisolid, a tablet, orsachet, a lozenge or a capsule. In alternative embodiments, thesecomponents are used in doses (e.g., unit dosages) of between about 10grams to 40 grams, or between about 20 grams to about 36 grams; or, atabout 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 or more grams.

Exemplary capsules of the invention are in the formulation described inExample 1, below. In alternative embodiments, these capsules (or otherunit dosage formulations, e.g., tablets, sachets, geltabs, lozenges andthe like) can be administered in a dosage (e.g., a unit dosage) regimenof from between about 10 capsules and 70 capsules (or other unit dosageformulations), or between about 24 to 36 capsules, at about 30 capsules(or other unit dosage formulations) per patient, or about 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 or more capsules (or other unitdosage formulations), or an adjusted number or unit dosages, or totaldosages, as required for an individual's (e.g., patients) needs.

For example, in constipated or bloated patients capsule (or other unitdosage formulations) numbers can be increased—and in one embodiment, isdone so during the actual preparation by the patient, so incorporating a‘graded-dosage’ concept. In those patients with soft, frequent motionsthey can decrease the number. The type of fluids ingested by the patientwith the capsules can be at the patient's discretion (e.g., tea, DietCoke, water, sugar-free juices or drinks) provided that no sugars orpotentially volatile agents are present. This greatly improves thepalatability of the bowel preparation process and hence compliance.Ideally it requires no more than about 2 litres (liters) of fluids to betaken by the patient and the composition achieves very satisfactorycleansing with watery stools and a clean caecum.

In one embodiment, the invention provides a dry composition to beencapsulated (or otherwise manufactured in a comparable unit dosageformulations, e.g., a geltab) in between 10 and 70 capsules (or otherunit dosage formulations) and to be ingested by individuals (e.g.patients) in various timing formats. It can be ingested as between about2 to 10, or between about 6 to 8 capsules (or other unit dosageformulations) every hour, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20 capsules (or other unit dosageformulations) or more per hour, in conjunction with oral fluids of thepatient's choice and can be used for colonoscopic preparation orpreparation for surgery or other procedures.

In alternative embodiments, the invention provides a cleansing solutionfor the colon for patients with constipation or bloating as a disorderto be treated long term. The individual (e.g., a patient) can ingestbetween 5 and 15 capsules (or other unit dosage formulations) per day tohelp regular bowel actions occurring. This treatment can be takenlong-term basis with safety.

Erythritol

In alternative embodiments, the invention provides compositionscomprising an erythritol, or (2R,3S)-butane-1,2,3,4-tetraol, orequivalent isomers or sugar substitute isoforms. The erythritolcomponent can make a contribution at several levels in this preparation.For example, while the invention is not limited by any particularmechanism of action, erythritol can promote the absorption ofelectrolytes in the small bowel which other bowel lavages generallydeplete in patients. This is achieved through proximal small bowelpassive diffusion utilizing non-saturable kinetics, thus providing adistinct advantage in better re-absorption of not only the polyolerythritol but also co-transporting electrolytes, notably sodium andpotassium; see e.g., Ross (1972) J. of Clin. Invest. 51:2414; Bernt(1996) Reg. Toxicol. and Pharmacol. 24:S191-S197, in alternativeembodiments, when the composition contains additional potassium, sodiumand magnesium, these electrolytes are preferentially reabsorbed in thesmall bowel through the action of erythritol. Thus, one of the majorproblems with bowel preparations can be minimized since patients havefewer episodes relating to dehydration, including headaches andlight-headedness. There also can be a reduction in nausea and vomitingotherwise experienced by patients taking many current bowel preparationsand hence this preparation is much more acceptable to patients.

Secondly, while the invention is not limited by any particular mechanismof action, erythritol can maintain renal homeostasis by being excretedpredominantly in the kidneys without promoting an osmotic diuresis, andthus does not lead to dehydration of the patient. Indeed, Erythritol isassociated with a higher urine osmolality and does not influencecreatinine, citrate, urea or electrolytes including sodium, potassium,chloride and phosphate; see e.g., Tetzloff (1996) Reg. Toxicol. &Pharmacol. 24:S286-S295; Bornet (1996) Reg. Toxicol. & Pharmacol.24:S296-S302; Node (1992) J. Nutri 122:1266-1272. Such conservation ofthe electrolytes and body water with normal serum osmolarity can reducethe risk of hypotension, hyponatraemia, nausea and vomiting that is seencommonly with other preparations currently on the market; see e.g.,Bornet (1996) supra. The reduction in hyponatraemia also can reduce therisk of more serious side effects of other preparations includingconvulsions and acute renal failure relating to phosphate toxicity.

Thirdly, while the invention is not limited by any particular mechanismof action, erythritol can be metabolically inert in an individual orpatient with a low caloric value and having no effect on blood sugar.All of the safety studies of erythritol show no toxicological effects,and erythritol does not have any carcinogenic, mutagenic or teratogenicpotential; see e.g., Munro (1998) Food Chem. Toxicol. 36;1139-1174.

Fourthly, while the invention is not limited by any particular mechanismof action, erythritol—unlike degradable and minimally-degradable sugarssuch as mannitol—is resistant to metabolism by bowel bacteria, withrecent studies showing no significant metabolism by faecal (fecal)flora; see e.g., Hiele (1993) Br. J. Nutr. 69:169-176; Arrigoni (2005)Br. J Nutr. 94:643-646. Hence, in one alternative embodiment (or use),there is no explosive potential in patients during colonoscopy andpolypectomy using electro-cautery. Erythritol can be completelyresistant to bacterial attack unlike the more easily fermentablesubstrates. Furthermore, while the invention is not limited by anyparticular mechanism of action, only about 10% of the ingestederythritol in this exemplary preparation actually enters the colon; seee.g., Arrigoni (2005) Br. J. Nutr. 94:643-648. In alternativeembodiments, individuals (e.g., patients) are administered between about1 to about 40 grams, or between about 8 to 15 grams, of erythritol (orequivalent isomers or sugar substitute or synthetic isoforms) per day;or, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39 or 40 or more grams, of erythritol (or equivalent isomers orsugar substitute or synthetic isoforms) are administered per day.

Erythritol can be produced, e.g., by any method known in the art, e.g.,as described in U.S. Pat. Nos. 6,074,857; 6,001,616; 5,962,287;5,981,241; 5,902,739.

In some embodiments, the composition includes sugar or polyol substituteisoforms. Suitable sugars include minimally degradable sugars (forexample sugars having a carbohydrate moiety that is substantiallyresistant to endogenous digestion in the gastrointestinal tract) anddegradable sugars. Suitable sugars and polyol substitute isoformsinclude xylose, xylotriose, oligosaccharides such asxylooligosaccharides, fructooligosaccharides, fructosans,galactooligosaccharides, mannitol, glucose, L-glucose, sucrose,fructose, galactose, lactose or lactulose. Suitable polyol substituteisoforms include glycol, glycerol, threitol, arabitol, xylitol, ribitol,mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactilol andpolyglycitol.

Bisacodyl

In alternative embodiments, the invention provides compositionscomprising a bisacodyl, or pyridin-2-ylmethanediyl)dibenzene-4,1-diyldiacetate, or 4,4′-(pyridin-2-ylmethylene)bis(4,1-phenylene) diacetate,or a bioequivalent diphenylmethane. In alternative embodiments, thebisacodyl or bioequivalent diphenylmethane is formulated at or less thanabout 25 mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5mg, 4 mg, 3 mg, 2 mg or 1 mg or less, or are between about 1 and 25 mgper dosage.

In alternative embodiments, a formulation or composition of theinvention comprises between about 10 mg to about 1, 2, 3, 4 or 5 or moregrams (g) bisacodyl, or between about 75, 80, 85, 90 or 100 mg to about150 to 200 mg (e.g., for a normal patient) bisacodyl, or between about100, 110, 120, 130, 140 or 150 mg to about 1, 2, 3, 4 or 4.5 g or morebisacodyl for a constipated patient

In one embodiment, a bisacodyl or a bioequivalent diphenylmethane isused in a preparation of the invention at a final dose of about 10 mgspread over the entire course of the ingestion; this can reduce any peakdosage levels at which side effects occur and exposes the gut to muchlower concentrations of bisacodyl than is currently available topatients for colonoscopy preparation or for constipation or bloatingtreatment. Hence the potential for cramping or adverse effects isminimized with this formulation.

In alternative embodiments, the bisacodyl is DULCOLAX™, DUROLAX™,FLEET™, ALOPHEN™ or CORRECTOL™.

Bisoxatin

In alternative embodiments, the invention provides compositionscomprising a bisoxatin (or2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatinacetate, or equivalent. In alternative embodiments, a formulation orcomposition of the invention comprises between about 10 mg to about 1,2, 3, 4 or 5 or more p/ams (g) bisacodyl, or between about 75, 80, 85,90 or 100 mg to about 150 to 200 mg (e.g., for a normal patient)bteacodyl, or between about 100, 110, 120, 130, 140 or 150 mg to about1, 2, 3, 4 or 4.5 g or more bisacodyl for a constipated patient

In alternative embodiments, the bisoxatin is LAXONALIN™, MARATAN™,TALSIS™, TASIS™.

Additional Optional Ingredients

In alternative embodiments, hexaminolevulinate, or CYSVIEW™, orhexaminolevulinate HCl, is added to a composition of the invention,e.g., a capsule or tablet, which can be ingested late in the preparationor dosage regimen. The amount that is required can be between about 5 mgand 500 gm, or about 100 g. Due to a large quantity of hexaminolevuliatepassing in the colon, a larger volume can therefore be included toincrease attachment to polyps. In some embodiments, only a small volumeof hexaminolevulinate is required, and it will take up no greater volumethan about 2 of the 900 mg capsules (e.g., 1.8 gm).

In alternative embodiments, simethicone (or any mixture ofpolydimethylsiloxane and silica gel) or smaller surfactant is added intoa composition of the invention; optionally between about 5 mg and 450 mgcan be added. In specific embodiments, 100 mg of simethicone is added tothe composition. The addition of lubricants such as glycerol or silconeto the formulation can also help with colonoscope insertion andfacilitation within the performance of the colonoscopy.

Unit Dosage Forms and Formulations and Delivery Vehicles

In alternative embodiments, a composition is manufactured, labeled orformulated as a liquid, a suspension, a spray, a gel, a geltab, asemisolid, a tablet, or sachet, a capsule, a lozenge, a chewable orsuckable unit dosage form, or any pharmaceutically acceptableformulation or preparation. In alternative embodiments, a composition ofthe invention is incorporated into a food, a feed, a drink, anutritional or a food or feed supplement (e.g., liquid, semisolid orsolid), and the like.

For example, a composition of the invention can be manufactured, labeledor formulated as an orally disintegrating tablet as described e.g., inU.S. Pat. App. Publication No. 20100297031. A composition of theinvention can be a polyo/thickened oil suspension as described in U.S.Pat. No. (U.S. Pat. No. ) 6,979,674; 6,245,740. A composition of theinvention can be encapsulated, e.g., encapsulated in a glassy matrix asdescribed e.g., in U.S. Pat. App. Publication No. 20100289164; and U.S.Pat. No. 7,799,341, A composition of the invention can be manufactured,labeled or formulated as an excipient particle, e.g., comprising acellulosic material such as microcrystalline cellulose in intimateassociation with silicon dioxide, a disintegrant and a polyol, sugar ora polyol/sugar blend as described e.g., in U.S. Pat. App. PublicationNo. 20100285164. A composition of the invention can be manufactured,labeled or formulated as an orally disintegrating tablet as describede.g., in U.S. Pat. App. Publication No. 20100278930. A composition ofthe invention can be manufactured, labeled or formulated as a sphericalparticle, as described e.g., in U.S. Pat. App. Publication No.20100247665, e.g., comprising a crystalline cellulose and/or powderedcellulose. A composition of the invention can be manufactured, labeledor formulated as a rapidly disintegrating solid preparation useful e.g.as an orally-disintegrating solid preparation, as described e.g., inU.S. Pat. App. Publication No. 20100233278. A composition of theinvention can be manufactured, labeled or formulated as a solidpreparation for oral application comprising a gum tragacanth and apolyphosphoric acid or salt thereof, as described e.g., in U.S. Pat.App. Publication No. 20100226866. A composition of the invention can bemanufactured, labeled or formulated using a water soluble polyhydroxycompound, hydroxy carboxylic add and/or polyhydroxy carboxylic acid, asdescribed e.g., in U.S. Pat. App. Publication No. 20100222311. Acomposition of the invention can be manufactured, labeled or formulatedas a lozenge, or a chewable and suckable tablet or other unit dosageform, as described e.g., in U.S. Pat. App. Publication No. 20100184785.A composition of the invention can be manufactured, labeled orformulated in the form of an agglomerate, as described e.g., in U.S.Pat. App. Publication No. 20100178349. A composition of the inventioncan be manufactured, labeled or formulated in the form of a gel orpaste, as described e.g., in U.S. Pat. App. Publication No. 20060275223.A composition of the invention can be manufactured, labeled orformulated in the form of a soft capsule, as described e.g., in U.S.Pat. No. 7,846,475, or U.S. Pat. No. 7,763,276.

In one embodiment, a composition of the invention is incorporated into afood, a feed, a drink, a nutritional or a food or feed supplement (e.g.,liquid, semisolid or solid), and the like, as described e.g., in U.S.Pat. App. Publication No. 20100178413. In one embodiment, a compositionof the invention is incorporated into (manufactured as) a beverage asdescribed e.g., in U.S. Pat. No. 7,815,956. For example, a compositionof the invention is incorporated into a yogurt, an ice cream, a milk ormilkshake, a “frosty”, “snow-cone”, or other ice-based mix, and thelike.

The polyols used in compositions of the invention can be micronizedpolyols, e.g., micronized polyols, e.g., as described e.g., in U.S. Pat.App. Publication No. 20100255307, e.g., having a particle sizedistribution (d₅₀) of from 20 to 60 μm, and a flowability below or equalto 5 s/100 g, or below 5 s/100 g.

The invention will be further described with reference to the followingexamples; however, it is to be understood that the invention is notlimited to such examples.

EXAMPLES Example 1 Exemplary Formulation of the Invention

Exemplary formulation 1 comprises:

Bisacodyl or Bisoxatin   10 mg, Magnesium sulphate 10.24 gm, SodiumSulphate  5.76 gm, Potassium Gluconate  4.4 gm, Erythritol 10.24 gm.

In alternative embodiments, for formulation 1, and other formulations ofthe invention, capsules and other unit dosage forms and formulations areformulated as described herein.

For example, in one embodiment, for diarrhea, capsules (or tablets,etc.) at a dosage schedule of four capsules every 20 minutes areadministered (e.g., self-administered by patient); in one embodiment,between about 25 and about 35 total capsules (or tablets, etc.) areadministered (e.g., self-administered by patient).

In one embodiment, for use in colonoscopy preparation, twenty-four (24)capsules are taken at intervals of between about 5 to 15 tabletscapsules (or tablets, etc.) with approximately liquid (e.g., two glassesof water or equivalent) per hour.

In one embodiment, for use in capsule endoscopy (e.g., for anaemia(anemia) investigation) preparation, between about 15 to about 35capsules of the capsules (or tablets, etc.) are administered, e.g.,self-administered; where in one embodiment, about 5 capsules (ortablets, etc.) are taken, or about 1, 2, 3, 4, 5, 6, 7, 6, 9 or 10 ormore capsules (or tablets, etc.) are taken, about every half an hour, orat about every 15 to 45 minutes, is taken until patient developsdiarrhea.

In one embodiment, for use in virtual colography preparation, patient isadministered, e.g., self-administered, about 8 capsules (or tablets,etc.) about every hour (or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12or more capsules (or tablets, etc.) are taken about every hour) withabout 2 litres of water or other fluids (or mixtures thereof). Diarrhoea(diarrhea) is expected to begin around the second hour; then will becomequite watery; the virtual colography can be carried out the followingday.

Exemplary formulation 2 comprises:

 10.0 mg Bisacodyl or Bisoxatin 10.24 gm  Magnesium Sulphate 5.76 gmSodium Sulphate 4.48 gm Potassium Gluconate 4.48 gm Sodium Chloride10.24 gm  Erythritol

Seven (7) patients have undergone bowel preparation using exemplaryformulation 2; results from evaluations: 2 have had excellent scores, 2have had good scores and 3 received fair scores, one of which had anobstructing rectal cancer and the other had a history of severeconstipation.

From a side effect point of view, the feedback has been reassuring,i.e., few side or not severe side effects were reported. All patients,especially those which have used previous bowel preparation products,agree that the capsules are much more pleasant to take (even if they aresubstantial in size): they experienced no adverse effects, apart fromthe expected mild abdominal pain, 2 out of 7 experienced mild to severeheadaches and attribute it to lack of food rather than as a result ofthe capsules themselves. Most patients also agree that the method waseasy to follow and worthwhile.

Overall, the capsules have been a success in eliminating unnecessary andunpleasant side effects which would usually cause patients to postponetheir procedures for as long as possible. This has a significant impacton the patient's well being as, polyps and other potential threats, canbe located and removed before they become life threatening.

They have also been successful in reducing the “grouse” (complaining)factor. The fact that (in one embodiment) the preparation comes in acapsulated form, draws the attention of patients with previous illexperiences with the sachet forms of the preparation. Since all agreethat they prefer the capsules and would use them again, the capsuleshave been successful in this matter as well.

Currently, these erythritol bowel preparation formulations of theinvention (e.g., as capsules) have shown adequate bowel clean out, withlittle to no side effects, and patients expressed a willingness to takethis form of this exemplary preparation again.

Further exemplary Formulations comprise(all formulations of theinvention optionally can be formulated as a food or a beveragesupplement, a dietary supplement, a liquid, an emulsion, a solution, apill, a tablet, a capsule, a powder or an equivalent):

Exemplary formulation 3 comprises:

 10 mg Bisacodyl or Bisoxatin 7.0 g magnesium sulphate 15.0 g  sodiumsulphate 3.0 g Potassium gluconate 3.0 g sodium chloride 3.0 gErythritol

Exemplary formulation 4 comprises:

 10 mg Bisacodyl or Bisoxatin 7 g magnesium sulphate 6 g sodium sulphate3.0 g   Potassium gluconate 3.0 g   sodium chloride 6 g Erythritol

Exemplary formulation 5 comprises:

10.0 mg Bisacodyl or Bisoxatin 13.24 gm  Magnesium Sulphate 5.76 gmSodium Sulphate 4.48 gm Potassium Gluconate 4.48 gm Sodium Chloride 7.24gm Erythritol

Exemplary formulation 6 comprises:

10.0 mg Bisacodyl or Bisoxatin 10.24 gm  Magnesium Sulphate 5.76 gmSodium Sulphate 4.48 gm Potassium Gluconate 4.48 gm Sodium Chloride10.24 gm  Erythritol

Exemplary formulation 7 comprises:

Bisacodyl or Bisoxatin 10 mg Mg Sulphate 7 g Sodium sulphate 15 gPotassium gluconate 3 g Sodium chloride 3 g Erythritol 3 g

Exemplary formulation 8 comprises:

1 capsule 32 capsules 40 capsules Sodium picosulphate 0.625 mg 20 mg 25mg Magnesium sulphate 156 mg 5 g 6.24 g Sodium sulphate 93.75 mg 3 g3.75 g Potassium gluconate 62.5 mg 2 g 2.5 g Mannitol 312.5 mg 10 g 12.5g Sodium chloride 93.75 mg 2 g 2.5 g Total 688.125 mg 22.02 g 27.525 g

Exemplary formulation 9 comprises:

1 capsule 25 capsules 28 capsules Sodium picosulphate 1.2 mg 30 mg 33.6mg Magnesium sulphate 320 mg 8 g 8.96 g Sodium sulphate 180 mg 4.5 g5.04 g Potassium gluconate 140 mg 3.5 g 3.92 g Mannitol 320 mg 8 g 8.96g Sodium chloride 140 mg 3.5 g 3.92 g Total 1.10 g 27.53 g 30.83 g

Exemplary formulation 10 comprises:

1 capsule 24 capsules 32 capsules Sodium picosulphate 1.2 mg 28.8 mg38.4 mg Magnesium sulphate 320 mg 7.68 g 10.24 g Sodium sulphate 180 mg4.32 g 5.76 g Potassium gluconate 140 mg 3.36 g 4.48 g Mannitol 820 mg7.68 g 10.24 g Sodium chloride 140 mg 3.36 g 4.48 g Total 1.10 g 26.43 g35.24 g

In alternative embodiments, the invention provides a combination ofexemplary formulations that are designed to be taken in sequence as partof a treatment or colonoscopy preparation regimen. For example, oneembodiment would have the patient taking the contents of a firstcontainer (e.g., a bottle, blister pack, and the like)) before thecontents of a second container. In one embodiment, contents of a firstcontainer would comprise or consist of capsules (or pills, tablets,geltabs, and the like) comprising the following exemplary formulation:Bisacodyl Magnesium sulphate, Sodium sulphate, Potassium gluconate,Sodium chloride and Erythritol, e.g., in the following exemplaryamounts:

Exemplary formulation 11comprises:

First bottle (e.g., having about 16 caps) Bisacodyl or Bisoxstin 10 mgMagnesium sulphate 2.95 g Sodium sulphate 6.32 g Potassium gluconate1.26 g Sodium chloride 1.26 g Erythritol 1.26 g

In one embodiment, these capsules could be a different color and/orshape than the capsules (or pills, tablets, geltabs, and the like) inthe second formulation (contained in the second container). In oneembodiment, the first container (e.g., a bottle) would have betweenabout 10 to 40 or more capsules, e.g., 10, 11, 12, 13, 14, 15, 16, 17,13, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or morecapsules. In one embodiment, the second container would have betweenabout 2 to 30 or more capsules, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32 or more capsules.

In one embodiment, the second container (e.g., a bottle) would compriseor consist of capsules (or pills, tablets, geltabs, and the like)comprising the following exemplary formulation: Magnesium sulphate,Sodium sulphate, Potassium gluconate, Sodium chloride and Erythritol,e.g., in the following exemplary amounts:

Exemplary formulation 12 comprises:

Second Bottle (e.g., having about 22 caps) Magnesium sulphate 4.05 gSodium sulphate 8.68 g Potassium gluconate 1.74 g Sodium chloride 1.74 gErythritol 1.74 g

In one embodiment, the invention provides methods for administering acombination of exemplary formulations that are designed to be taken insequence (a so-called “spilt protocol”) as part of a treatment or acolonoscopy preparation regimen, comprising administering (ofinstructing to the patient to sell-administer) the contents of the firstcontainer, then several hours later between about 6 to 24 hours later)or the next day (e.g., the morning of the procedure, e.g., acolonoscopy) the contents of the second container.

In alternative embodiments, the first container (e.g., a bottle)comprises capsules (or pills, tablets, geltabs, and the like) havingexemplary formulation 11, and the second container (e.g., a bottle)comprises capsules (or pills, tablets, geltabs, and the like) havingexemplary formulation 12, and the first container has about 16 capsulesto be taken or administered first, and the second container has about 22capsules to be taken later, e.g., several hours later (e.g., betweenabout 6 to 24 hours later) or the next day (e.g., the morning of theprocedure, e.g., a colonoscopy).

In another embodiment, the first container comprises capsules (or pills,tablets, geltabs, and the like) having exemplary formulation 11, and thesecond container comprises capsules (or pills, tablets, geltabs, and thelike) having exemplary formulation 12, and the first container has about32 capsules to be taken or administered first, and the second container(e.g., a bottle) has about 6 capsules to be taken later, e.g., severalhours later (e.g., between about 6 to 24 hours later) or the next day(e.g., the morning of the procedure, e.g., a colonoscopy).

In another embodiment, the kit comprises a container (e.g., a bottle)comprising or consisting of capsules (or pills, tablets, geltabs, andthe like) comprising the following exemplary formulation: Bisoxatin,Magnesium sulphate, Sodium sulphate, Potassium gluconate, Sodiumchloride, Erythritol, and Simethicone, e.g., in the following exemplaryamounts:

Exemplary formulation 13 comprises (per 24 capsules)

Magnesium Sulphate 7 gm Sodium Sulphate 3 gm Potassium Gluconate 3 gmSodium Chloride 4 gm Erythritol 2 gm Bisoxatin 240 mg Simethicone 100 mg

In one embodiment, for use in capsule endoscopy (e.g., for anaemia(anemia) investigation) preparation, comprises between about 15 to about35 capsules of the capsules (or tablets, etc.) are administered, e.g.,sell-administered; where in one embodiment, about 5 capsules (ortablets, etc.) are taken, or about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ormore capsules (or tablets, etc.) are taken, about every half an hour, orat about every 15 to 45 minutes, is taken until patient developsdiarrhea.

Example 2 Clinical Investigation of an Exemplary Formulation of theInvention

The following example demonstrates that the compositions of theinvention are effective and well tolerated for use in colonoscopypreparation.

A clinical investigation in a male volunteer comprising of the abovecomposition (the exemplary formula of Example 1) was conducted. A lightbreakfast in accordance to colonoscopy preparation orders was undertakenprior to the intake of the bowel lavage. Twenty-four (24) capsules ofthe above formulation were taken at intervals of eight (8) capsules withtwo glasses of water per hour approximately. First bowel movement wereobserved approximately 30 minutes after the second dose of eight(8)capsules, and desired stool consistency, defined as clear waterystool with no discernible form was observed approximately two hoursafter last dose intake. The formulation was tolerated well and noheadaches, nausea or other adverse effects were observed whilstundertaking towel lavage preparation.

Example 3

Use of an Exemplary Formulation of the Invention to Treat a Non-SpecificAbdominal Pain ‘Syndrome’

The following example demonstrates that the compositions of theinvention are effective for treating or ameliorating non-specificabdominal pain syndrome.

A 32 yr old female patient was admitted with recurrent abdominal pain;but more intense in severity on this occasion to the emergencydepartment. The pain was described as generalized with greater attentionon the left iliac fossa, but could also pass through to the back and wasat times aggravated by eating. Numerous investigations failed to show anorganic cause including CT scan MRI, β-HCG and blood tests. She wasdiagnosed with non-specific abdominal pain (syndrome).

In the absence of other diagnoses, the patient was given treatment toflush out the bowel flora in attempt to reduce the pain. She was given 8capsules of this inventions exemplary formula comprising erythritol andbisacodyl, the formula of Example 1, and started defecating waterystools within 1 and a half hours. The reduction in pain took about 2-3hours and by the time she had passed 11 stools the pain was virtuallygone. This diagnostic therapy was able to refer her to agastroenterologist for further investigations.

Example 4 Use of an Exemplary Formulation of the Invention in an AcuteCase of Constipation

The following example demonstrates that the compositions of theinvention are effective for treating or ameliorating acute cases ofconstipation or bloating.

73 year old otherwise well male patient with recently developed backpain prescribed with codeine related medication presented with acutecase of constipation. He was seen by his doctor and given laxativeswhich did not help him. On examination he had a soft abdomen, rectalexam was normal and abdominal x-ray showed fecal loading in ascendingcolon with no bowel obstruction.

Patient was treated with bowel preparation composition as listed inExample 1 using 8 capsules every 8 hours. His first stool was delayedfour and a half hours but thereafter every 15-20 minutes ha startedpassing stools which ultimately became watery. His symptoms disappearedvirtually overnight and he followed up with 8 capsules twice daily ofthe same product for the next four weeks and was able to defecate withease.

Example 5 Use of an Exemplary Formulation of the Invention in theTreatment of Traveller's Diarrhea

A 34 year old male was given the bowel preparation with 32 capsules butalso with rifaximin (e.g., XIFAXAN™) to a total dose of 1 gm spreadacross the 32 capsules. This was in preparation for an overseas trip toVietnam. Upon returning from Vietnam he recounted how he developedcramping and diarrhea with severe pains that lasted for a couple ofdays. Initially reticent about taking the capsules, he finally startedtaking the capsules at a dosage schedule of four capsules every 20minutes until he finished. With the starting of the flow of the diarrheasecondary to the capsules he flushed out his bowel, the pain wasrelieved within 4 to 6 hours completely, and continued on with his tripsthrough Asia without further incidence.

Example 6 Use of an Exemplary Formulation of the Invention inPreparation for Capsule Endoscopy

A 72 year old patient underwent Capsule Endoscopy for anaemiainvestigation. He had previously had normal endoscopy and colonoscopyand a bleeding sits was being sought in the small bowel. The patient wasgiven 25 capsules of the composition as listed in Example 1. He took 5capsules every half an hour until he developed diarrhea.

Capsule endoscopy was successful in allowing the capsule to traverse theentire small bowel whereas in the pest the capsules ran out of batterylife in the mid small bowel. The patient had had small bowel transitwhich was slow but when the bowel was prepared the capsule was able totraverse the bowel more rapidly and recorded photographs from the entiresmall bowel. Hence an example of the usefulness of the bowel prep inachieving complete small bowel examination in patients with otherwiseslow small bowel transit.

Example 7 Use of an Exemplary Formulation of the Invention for VirtualColography

A 54 year old patient passed blood rectally. He did not want to undergocolonoscopy and chose to have a virtual colography. He was given thepreparation contained in Example 1 taking 8 capsules every hour with 2litres of water or other fluids. His diarrhoea began around the secondhour then became quite watery then he was very wail prepared for thevirtual colography which was carried out successfully in the radiologydepartment on the following day. No particulate stool matter werepresent on view during the virtual colography.

Example 8

Use of an Exemplary Formulation of the Invention or Colon PreparationPrior to Colonoscopy

The following example demonstrates that the compositions of theinvention are effective for colon preparation prior to colonoscopy. Thisexample describes the effective use of picosulphate capsules for colonpreparation prior to colonoscopy:

1 capsule 32 capsules 40 capsules Sodium picosulphate 0.625 mg 20 mg 25mg Magnesium sulphate 156 mg 5 g 6.24 g Sodium sulphate 93.75 mg 3 g3.75 g Potassium gluconate 62.5 mg 2 g 2.5 g Mannitol 312.5 mg 10 g 12.5g Sodium chloride 93.75 mg 2 g 2.5 g Total 688.125 mg 22.02 g 27.525 g

1 capsule 25 capsules 28 capsules Sodium picosulphate 1.2 mg 30 mg 33.8mg Magnesium sulphate 320 mg 8 g 8.96 g Sodium sulphate 180 mg 4.5 g5.04 g Potassium gluconate 140 mg 3.5 g 3.92 g Mannitol 320 mg 8 g 8.96g Sodium chloride 140 mg 3.5 g 3.92 g Total 1.10 g 27.53 g 30.83 g

1 capsule 24 capsules 32 capsules Sodium picosulphate 1.2 mg 28.8 mg38.4 mg Magnesium sulphate 320 mg 7.68 g 10.24 g Sodium sulphate 180 mg4.32 g 5.76 g Potassium gluconate 140 mg 3.36 g 4.48 g Mannitol 820 mg7.68 g 10.24 g Sodium chloride 140 mg 3.36 g 4.48 g Total 1.10 g 26.43 g35.24 g

The study described in this example evaluated the efficacy and safety ofpicosulphate capsules as a bowel preparation; and assessed the sideeffects and tolerability of picosulphate capsules as a bowelpreparation.

Patients were from a clinic who were scheduled to undergo a colonoscopy,Sample Size: 55 patients correctly followed all preparation proceduresto completion. Treatment and dosage: “24 capsule” version (noted above)picosulphate capsules administered to 23 patients; and “32 capsule”version (noted above) picosulphate capsules administered to 32 patients.

Efficacy Data: Patient Evaluation Form was assessed for compliance andtolerance using score ratings. Doctor Evaluation Form and AnaesthetistEvaluation Form were used to assess efficiency of colonic cleansingduring colonoscopy.

Safety Data: Adverse events (AE) were noted by the patient using thePatient Evaluation Form.

Colonoscopic surveillance was used in this study: it is considered to bethe gold standard for assessing colonic mucosa. Early detection andprevention of bowel cancers is dependent wholly on colonoscopies and anadequately prepped bowel. Poorly prepped bowels increase the risk ofmissed lesions, longer procedure duration and a greater need for repeatcolonoscopies.¹

In alternative embodiments, formulations of this invention combine highefficacy with improved tolerability and palatability, whilst preventingelectrolyte disturbances; and these properties can address the problemof bowel preparations having: poor palatability, poor patienttolerability and/or causing severe electrolyte disturbances.

In alternative embodiments, formulations of this invention prepare acolon for colonoscopy by reliably emptying the colon of all (orsubstantially all) faecal matter with no gross or histologicalalteration of the colonic mucosa. In alternative embodiments,formulations of this invention are well tolerated by the patient, arepalatable, and do not cause any electrolyte shifts.

In alternative embodiments, formulations of this invention, e.g., thepicosulphate capsules embodiments of this invention, use (comprise)encapsulated sodium picosulphate together with the minimally degradablesugar mannitol to purge the bowel. While the invention is not limited byany particular mechanism of action, sodium picosulphate can work bystimulating the nerve endings in the intestinal wall, hence promotingcolonic motility and inhibiting electrolyte and water reabsorption; and,mannitol can work to purge the bowel osmotically. While the invention isnot limited by any particular mechanism of action, water content isincreased in the colon by mannitol's ability to attract extracellularfluid efflux through the colon wail and maintain oral fluids in thelumen.⁵

In alternative embodiments, formulations of this invention areencapsulated, and encapsulation of these exemplary formulations cansignificantly increase preparation palatability, in alternativeembodiments, formulations of this invention solve the palatabilityrecurring problem (where bowel preparations either tasted too salty orrequired copious amounts of liquid to be consumed). In alternativeembodiments, formulations of this invention, this is overcome byencapsulation of the ingredients; a highly palatable delivery systemwhich may increase patient compliance.

In alternative embodiments, encapsulation of exemplary formulations alsohelps to maintain efficacy of the bowel preparation, as the sodiumpicosulphate does not begin working until it has reached the gut. It ismalty absorbed in the small intestine where it is most required for aneffective clean out.

In alternative embodiments, electrolytes are included in exemplarypreparations to reduce electrolyte loss during bowel purgation andcreate an iso-osmotic environment, thereby reducing the risk ofelectrolyte disturbances. In alternative embodiments, various salts areused to decrease the symptoms of dehydration and other side effects, andthus improve tolerability of the bowel preparation.

Method

Participants: 55 patients correctly followed all preparation proceduresto completion. All 55 patients were aged between 18 to 70 years old andwere scheduled to undergo a colonoscopy at a clinic.

Investigational Procedures: Patients aged 18 to 70 scheduled to undergoa colonoscopy at a clinic were informed of a new investigationalalternative to the currently marketed bowel preparations. Fully informedconsent was obtained and patients were given either the “24” formulationor the “32” formulation (described above) picosulphate capsules. Anadministration protocol and a Patient Evaluation Form assessing patientcompliance and tolerability were also given to the patient.

Patients then returned to the clinic for their scheduled colonoscopies.Completed Patient Evaluation Forms were collected and a colonoscopy wasperformed. Doctor and anaesthetist evaluated the efficacy of thepicosulphate capsules using the Doctor Evaluation Form and AnaesthetistEvaluation Form; both forms based on the Ottawa Bowel Preparation Scale.Doctor and anaesthetist assessed the cleanliness of five sections of thebowel—the rectum, sigmoid/descending colon, transverse colon, ascendingcolon/hepatic flexure, and caecum. The volume of fluid in the colon wasalso assessed.

Evaluation Scoring: The bowel preparation evaluation scoring methodsemployed were based on the Ottawa Bowel Preparation Scale and used afive point rating system. Five sections of the bowel (rectum,sigmold/descending colon, transverse colon, ascending colon/hepaticflexure, and caecum) were rated from 0-4 for cleanliness (0=Excellent,1=Good, 2=Fair, 3=Poor, 4=Inadequate) independently by both Doctor andAnaesthetist.

The volume of fluid present in the entire colon was also assessed usinga three point rating system. Volume of fluid was rated from 0-2 (0=smallvolume, 1=medium volume, 2=large volume) independently by both doctorand anaesthetist,

Scores rating the cleanliness of each section of the colon and volume offluid present were then combined for each patient to produce a totalscore. An average was then obtained from the doctors' and anaesthetists'total scores and general evaluation grade was assigned based on thefollowing grading system:

Average Total Score General Evaluation Grade 0-5 EXCELLENT 6-9 GOOD10-13 FAIR 14-19 POOR 20-22 INADEQUATE

Results Patient Evaluation:

All 55 patients were able to complete the picosulphate capsulepreparation without difficulty with 43/55 (78.2%) patients and 12155(21.8%) patients finding the preparation “easy” and “somewhat easy” tocomplete, respectively.

54/55 (98.2%) of patients reported that they would prefer to take thepicosulphate capsules again for future procedures. Of these patients whostated that they would use picosulphate capsules again 42 (77.8%) havepreviously taken other bowel preparations.

Patient compliance was also high with all 55 patients correctlyfollowing the picosulphate capsule administration protocol.

Doctor and Anaesthetist Evaluatation:

47/55 (85.5%) patients who trialed the picosulphate capsules achieved anExcellent/Good general evaluation grade (Average total score of 0-9) forcleanliness of the whole bowel. The average doctor and an anaesthetistscores for rating the cleanliness of the rectum, sigmoid/descendingcolon, transverse colon, ascending colon/hepatic flexure, and caecumduring colonoscopy were 0.69, 0.71, 0.70, 0.91, and 1.17, respectively(0=Excellent, 1=Good). The average doctor and an anaesthetist score forrating the volume of fluid present in the entire colon was 0.57,representing a small to medium volume.

Adverse Events:

No serious adverse events were reported and capsules were well toleratedby patients. Of the adverse events experienced, effects were mild andtransient in nature. 22 patients reported a mild headache, 19 patientsreported nausea, and 2 patients reported dizziness and vomiting. 8patients experienced no side effects at all.

DISCUSSION AND CONCLUSION

In overall cleansing of the colon prior to colonoscopy, picosulphatecapsules were effective with a majority of patients (85.5%) achieving anExcellent/Good overall evaluation grade. Doctor and anaesthetist scoresrating the rectum, sigmoid/descending colon, transverse colon, ascendingcolon, and caecum did not reflect any significant differences inpicosulphate's ability to effectively cleanse different sections of thecolon. All sections of the colon scored en average between 0.69 and 1.17representing an Excellent to Good evaluation score. Volume of fluidpresent within the entire colon scored an average of 0.57 representing asmall to medium volume of fluid present.

Five patients scored a “Fair” evaluation grade, 4 of whom always presentwith a poorly prepped bowel despite using different preparations. 3patients scored a “Poor” evaluation grade, 2 of whom had an ongoinghistory of severe constipation.

All adverse events were mild in nature and transient. All adverse eventsreported were also expected and are frequently reported after completionof currently marketed bowel preparations.² 8/55 (14.5%) patientsreported no side effects at all after completion of picosulphatecapsules.

Despite adverse events, tolerability and palatability of picosulphatecapsules were significantly high in all patients with 100% (55/55) ofpatients finding the capsules easy or somewhat easy to take and 98.2%(54/55) of patients reporting preference for picosulphate capsules overalternative bowel preparations. This was also reflected in the highpatient compliance with all 55 patients correctly and ably following thepicosulphate preparation protocol.

In conclusion, these clinical observations demonstrated thatpicosulphate capsules are an effective, safe and tolerable new bowelpreparation alternative for patients.

Example 9 Exemplary Formulation—Clinical Observations:

This example provides information and clinical results demonstrating theefficacy of an exemplary formulation 13 of the invention;

Bisoxatin 240 mg Magnesium sulphate 7 gm Sodium sulphate 3 gm Potassiumgluconate 3 gm Sodium chloride 4 gm Erythritol 2 gm

32 patients aged between 18 to 70 years scheduled to undergo acolonoscopy underwent the capsule preparation after being informed of anovel bowel preparation (exemplary formulation 13 of this invention)which offered an alternative to currently marketed bowel purgatives.Written informed consent was obtained and patients were given 23 capsuleformulation containing 240 mg bisoxatin. Patients were also given anadministration protocol, patient questionnaires and a drinking log tocomplete. Patients commenced bowel purgatives at 2 pm in the afternoon,and were allowed carbonated beverages that were artificially sweetenedin their fluid only diet.

Patients returned to the Clinic for their colonoscopies and completedpatient questionnaires were collected. Doctor and anaesthetist evaluatedthe cleanliness of the bowel independently, once again using themodified Ottawa bows/scale using a five point rating system andevaluating 5 sections of the bowel; rectum, sigmold/descending colon,transverse colon, ascending/hepatic flexure and caecum.

30/32 patients were given an ‘excellent/good’ rating and 31/32 of thepatients reporting that they would prefer to take the capsules againwith 14/31 of those patients reporting having previously taken otherbowel purgatives.

No serious adverse events were reported with the most common beingnausea and headaches, however these adverse effects were consideredtransient in nature.

REFERENCES

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A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. (canceled)
 2. A composition comprising: (i) bisoxatin, or bisoxatinacetate, (ii) erythritol, (iii) at least one disintegrant, and (iv) oneor more pharmaceutically acceptable salts, wherein the pharmaceuticallyacceptable salt or salts comprise at least one sodium salt, at least onepotassium salt and at least one magnesium salt.
 3. The composition ofclaim 2, wherein the composition is formulated in at least 9 unitdosages.
 4. The composition of claim 2, wherein the disintegrantcomprises a natural starch, a maize starch or potato starch; a directlycompressible starch; a modified or pre-gelatinized starch, acarboxymethyl starch, a sodium starch glycolate; a natural or achemically-modified cellulose, a crosslinked sodium carboxymethylcellulose, a croscarmellose sodium, a low substituted hydroxypropylcellulose; a microcrystalline cellulose; a gum, an agar gum, a guar gum;an alginic acid or salts thereof; an acetate or a citrates; an aluminumoxide; a synthetic polymer, a cross-linked polyvinylpyrrolidone and/or acrospovidone.
 5. The composition of claim 2 wherein the compositioncomprises about 240 milligrams (mg) of bisoxatin, or bisoxatin acetate.6. The composition of claim 2, wherein the composition comprises about 1g of erythritol.
 7. The composition of claim 2, wherein the compositioncomprises about 25 g or more of the one or more pharmaceuticallyacceptable salts.
 8. The composition of claim 2, wherein the sodium saltis a sodium sulfate.
 9. The composition of claim 2, wherein the sodiumsalt is a sodium starch glycolate.
 10. The composition of claim 2,wherein the potassium salt is potassium sulfate.
 11. The composition ofclaim 2, wherein the magnesium salt is magnesium sulfate.
 12. Thecomposition of claim 2, wherein the composition is formulated for use asa purgative, a colonic cleanser, or for orthostatic lavage.
 13. Apharmaceutical composition comprising a composition as defined in claim2 and a pharmaceutically acceptable excipient.
 14. The pharmaceuticalcomposition of claim 13, wherein the pharmaceutical composition ismanufactured, labeled or formulated as a plurality of tablets orcapsules.
 15. The pharmaceutical composition of claim 13, wherein thepharmaceutical composition is administered in a dosing regimen of about36 tablets or capsules.
 16. The pharmaceutical composition of claim 13,wherein the pharmaceutical composition or formulation is manufacturedwith an encapsulating material.
 17. A method of performing a procedureinvolving the intestine or colon on a subject, comprising administeringa first composition comprising the composition of claim 2, optionallywherein the subject is a human or an animal.
 18. The method of claim 17,wherein the procedure comprises a colonoscopy, an enteroscopy, anendoscopy, a capsule endoscopy, a viewing of the intestinal or colonicmucosa, a surgical procedure involving the intestine or colon, or aradiological procedure involving the intestine or colon to an individualin need thereof.
 19. A method for the amelioration, treatment and/orprevention of constipation or bloating in a subject, comprisingadministering the composition of claim 2 to the subject in need thereof.20. A method for the treatment of abdominal pain in a subject,comprising administering the composition of claim 2 to the subject inneed thereof.
 21. A method for the amelioration or treatment of a boweldisease in a subject, comprising administering a composition of claim 2to the subject in need thereof.
 22. A package or kit comprising: thecomposition of claim 2 and instructions for its use.
 23. The package orkit of claim 22, wherein the composition is contained within a firstcontainer, wherein the package or kit further comprises at least asecond container comprising the composition of claim 2, and the contentsof the two containers are designed to be taken in sequence.